a source of funding for translational medicine in...

A Source of Funding

for Translational Medicine

in Diagnostics

The Biomarker Factory Provides Funding and Expertise for

Bringing Biomarkers to Clinical Practice

Jeffrey Shuster, PhD, General Manager [email protected]

Translational Medicine in Diagnostics

A diagnostic is only of use if it changes clinical practice


One metric of state-of-the-art

The Biomarker Factory is a Company

Jointly Founded and Co-owned by

Laboratory Corporation of America Holdings (LabCorp)

and Duke Medical Strategies, an Affiliate of Duke University

The Biomarker Factory

The Biomarker Factory Provides Funding and

Expertise in Translational Medicine in Diagnostics

Access to a Unique Source of Large Population Biospecimens

Measurement to Understand the Reclassification of Disease Of Cabarrus / Kannapolis

A large population longitudinal study to reclassify health and disease Goal of 50,000 participants in the study >300,000 biospecimens to be available for the Biomarker Factory

Organization and Operations

The Biomarker Factory is comprised of a Board of Managers, a Steering Committee, and a General Manager Projects are solicited from both open announcements and specific requests for proposals The proposal process is interactive

The research is conducted at the funded institution (The Biomarker Factory does not provide laboratory or clinical services)

The work is funded under a sponsored research agreement It is goal oriented and actively managed

Robert Califf, MD

Director, Duke Translational Medicine Institute

Vice Chancellor for Clinical Research

Donald F. Fortin, M.D. Professor of Cardiology

Michael Kastan, MD, PhD

Executive director of the Duke Cancer Institute

Professor of Pharmacology and Cancer Biology

Professor of Pediatrics

David Goldstein, PhD

Director, Duke Center for Human Genome Variation

Richard and Pat Johnson Distinguished University

Professor

David King

President and

Chief Executive Officer

Laboratory Corporation of America Holdings

Andrew Conrad, PhD

Executive Vice President

Chief Scientific Officer


and National Genetics Institute

Mark Brecher, MD

Senior Vice President

Chief Medical Officer


Board of Managers

Steering Committee

David Johnston, PhD

Senior Vice President,

Global Head, LabCorp Clinical Trials


Christy Marshuetz Ferguson, PhD, MBA

Associate Vice President

Corporate Development


Victoria Christian

Chief Operating Officer,

Duke Translational Research Institute

Executive Manager, The MURDOCK Study

Bryan Baines, RPh

Associate Director, Duke University

Office of Licensing and Ventures

Jeffrey Shuster, PhD


General Manager

Biomarker Factory Funding

Biomarker Factory Funding

• Funding is provided to researchers for specific projects

• Projects can be funded up to a maximum of 2 years

• Funding is open to academic, non-profit, or for-profit institutions in the United States

• Proposal are solicited from open announcements and specific requests for proposals

• Proposals are accepted and reviewed in a 2-stage process on a rolling basis

• Funding is provided as sponsored research

Sponsored Research Approach

Milestones Driven Timelines Objective Success Criteria Defined Project has Active Project Management

Brief Monthly Progress Reports Interim Report and Analysis Project Meetings

Milestone and Timeline Examples

Milestone 6: Using q-PCR demonstrate the ability to distinguish between cohort A and cohort B, in sample sizes of at least n=20 in each class, as defined by AUC by ROC analysis of at least 0.80.

Business Model FAQs (available on the website, www.biomarkerfactory.com)

Who owns the Intellectual Property for Biomarker Factory funded projects?

If there is prior intellectual property (IP), the Biomarker Factory will have the option to license the pre-existing IP

related to the funded project. If an invention is made arising from a Biomarker Factory funded project, the

Biomarker Factory will be granted an option to license the intellectual property for the invention.

Can I publish discoveries made from Biomarker Factory funding?

Yes, publications and presentations are highly encouraged. It is important to protect the intellectual property,

and there is a waiting period to review any disclosures before presentation or publication to give time to file

patents if needed.

Does LabCorp have rights to Intellectual Property licensed by the Biomarker Factory?

Yes, LabCorp has a first option to license inventions owned by or licensed to the Biomarker Factory with regard

to Biomarker Factory funded projects.

Does LabCorp have the ability to commercialize Biomarker Factory funded inventions?

Yes, LabCorp is one of the largest clinical diagnostic laboratories in the world. LabCorp also has a global

network of labs for clinical trials.

The Proposal Process

1. Discuss Ideas with the Biomarker Factory General Manager

2. Submit a Project Concept Form

3. Project Concept review Q&A responses

4. Submit Full Proposal

5. Proposal review Q&A responses

1. Discuss Ideas with the Principal Investigator

2. Preliminary Review

3. Steering Committee Concept Review

4. Steering Committee Proposal Review

5. Recommendation to Board of Managers

6. Final decision of the Board of Managers

Principal Investigator

Biomarker Factory

Requests for Proposals

What types of projects are funded by the Biomarker Factory?

Disease diagnosis

Prognosis, for selection of treatment

Predictive, for optimizing therapy

Companion diagnostics for personalized medicine

All disciplines of medicine

Assay technologies suitable for use in clinical practice

Projects that identify or validate

biomarkers in clinical materials

Areas of Interest for Proposals

Chronic disease Cardiovascular Diabetes Mental health Cancer Arthritis Autoimmune diseases

Acute illness Cardiovascular events Infectious disease Cancer Toxicology Trauma

Health Nutrition Aging Microbiomes Immune system functions Performance training


Biomarker Factory Project Concept Components

1. Clinical need

What is the medical need for a new test over and above current clinical practice? 2. Patient population to be tested

What patient criteria will a physician use to order the test? 3. Actionable in clinical practice

Based on the test result, what will the physician do differently than he/she does today? 4. Number of patients

How many patients are estimated to be tested and how often?

Four Questions


A diagnostic is only of use if it changes clinical practice.

A focus on the utility of the biomarker

Diagnostic, prognostic, predictive, or companion

Screening in the general population

Screening in at risk populations

Diagnosis in symptomatic patients

One biomarker may have more than one utility and can be used in multiple tests and product lines.

Patient stratification to prescribe drug treatment

Drug efficacy

Drug side effects/toxicity

Experimental Design

Have the right specimens, and have enough of them

Pre-define the target patient population

Do not settle for samples of convenience

o You cannot make a good test with bad specimens

In translational work, very careful attention to detail is necessary in sourcing specimens

Make sure you understand all possible confounding variables

Understand the possible limitations of retrospective studies

Quality assurance for all samples in experimental design

Understand potential regulatory affairs issues up front

Consider Design Options Early

Enlist biostatisticians throughout the discovery phase

Plan biomarker discovery as close to clinical specimens as possible

If the test will need clinical parameters

Include the clinical parameters in the discovery phase

Does the new test out-perform current state of care

Sensitivity, specificity, PPV, NPV

ROC analysis, area under the curve

Calibration, reclassification

Costs of false positive and false negative results

Frequentist and Bayesian Outlooks

The p-value of a test of the null hypothesis that there is no difference was p<.05. Therefore, the test result means...

Taking into account the prior risk factors and symptoms, the test result means...

Laboratory Analysis is Often Frequentist

Clinical Diagnosis is Often Bayesian

A Frequentist and Bayesian go on a fishing expedition.

What is the probability of catching a red or black drum?

Sensitivity, Specificity, and Positive and Negative Predictive Values

If the test has 95% sensitivity 95% specificity it looks like this:

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

55%

60%

65%

70%

75%

80%

85%

90%

95%

100%

Prevalence

PPV - NPV

PPV NPV

Positive Predictive Value = 0.70

Diabetes screening in patients > 20 years of age

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

1.10

1.20

0.0

00

1

0.0

01

0

0.0

10

0

PPV NPV

or like this:

Positive Predictive Value = 0.004

Ovarian cancer screening in asymtomatic women age 50

Medical Need and Market Opportunity • Clinical need • Number of patients that will be tested

Technology • Can technology be adapted to clinical practice (disruptive technology thinking is not bad)

Products • What is the format of the test going to look like • How much will it cost to make it

Regulatory • Companion diagnostic or stand alone • IVD (FDA) or LDT (CLIA)

The Biomarker Factory A Project Concept View in 1-2 Pages

Intellectual Property • Who owns the technology • Will licenses be required

Competition

• Competitors • Technologies

Management

• Good ideas translate with good management • To whom and when does the baton get passed

Financing • How much will be needed • Where will it come from

What is Competing Technology?

Gene-by-gene Genome sequencing Gene panels

Daguerreotype Digital photography Film

Western blots Flow cytometry ELISA

Gene chips Micro/nano beads q-PCR

IHC H&E FISH

Technology should provide a best and economic use for the end user.

Examples

1. Questions/comments from Project Concept reviews.

3. How long does it take from discovery to clinical utility?

4. Biomarker Factory funded projects.

2. A few comments on biomarkers for clinical trials.

A Few Questions on the use of Biomarkers in Clinical Trials

At what stage of your clinical trial would you add a biomarker? Would you use a non-validated biomarker in a clinical trial? Would you not use a validated biomarker in a clinical trial?

HER2 Protein Amplification and a Decision to Treat

Clinical Utility A decision to

TREAT

Time from discovery to

clinical utility INCLUDING a new drug

13 years

Breast Cancer

Nucleic Acids Res. 1985 Dec 9;13(23):8477-86. Human tumor cell lines with EGF receptor gene amplification in the absence of aberrant sized mRNAs. King CR, Kraus MH, Williams LT, Merlino GT, Pastan IH, Aaronson SA. Abstract A survey of human tumor cell lines for increased PDGF or EGF receptors identified 5 lines which bind from 6 to 13 times more EGF than normal human fibroblasts. Immunoprecipitation analysis links the elevated binding activity to increased quantities of the EGF receptor protein. EGF receptor gene amplification was detected in 2 of the cell lines. No evidence for EGF receptor gene rearrangements was found at the level of DNA or RNA structure. The results suggest that elevated levels of EGF receptor can be associated with at least three distinct mechanisms. These include gene amplification accompanied by rearrangement, gene amplification without accompanied alteration of mRNA transcripts, and extensive

expression without gene amplification.

Nature. 1986 Jan 16-22;319(6050):226-30. The neu oncogene encodes an epidermal growth factor receptor-related protein. Bargmann CI, Hung MC, Weinberg RA. Abstract The neu oncogene is repeatedly activated in neuro- and glioblastomas derived by transplacental mutagenesis of the BDIX strain of rat with ethylnitrosourea. Foci induced by the DNAs from such tumours on NIH 3T3 cells contain the neu oncogene and an associated phosphoprotein of relative molecular mass 185,000 (p185). Previous work has shown that the neu gene is related to, but distinct from, the gene encoding the EGF receptor (c-erb-B). Here we describe a neu complementary DNA clone isolated from a cell line transformed by this oncogene; the clone has biological activity in a focus-forming assay. The nucleotide sequence of this clone predicts a 1,260-amino-acid transmembrane protein product similar in overall structure to the EGF receptor. We found that 50% of the predicted amino acids of neu and the EGF receptor are identical; greater than 80% of the amino acids in the tyrosine kinase domain are identical. Our results suggest strongly that the neu gene encodes the receptor for an as yet unidentified growth factor.

Personalized Medicine for Hepatitis C Antiviral Treatment

Medical need:

Treat patients that have a high chance of benefit

Challenges of PegIFN + ribavirin antiviral treatment:

Only 40-50% of patients with genotype 1 HCV show response

Long, arduous course of treatment (48 week regime)

Adverse effects, including anemia, can limit treatment

Hepatitis C Treatment

Biomarker to Clinical Practice in a year.

Nature. 2009 Sep 17;461(7262):399-401. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, Heinzen EL, Qiu P, Bertelsen AH, Muir AJ, Sulkowski M, McHutchison JG, Goldstein DB. SourceInstitute for Genome Sciences & Policy, Center for Human Genome Variation, Duke University, Durham, North Carolina 27708, USA. Abstract Chronic infection with hepatitis C virus (HCV) affects 170 million people worldwide and is the leading cause of cirrhosis in North America. Although the recommended treatment for chronic infection involves a 48-week course of peginterferon-alpha-2b (PegIFN-alpha-2b) or -alpha-2a (PegIFN-alpha-2a) combined with ribavirin (RBV), it is well known that many patients will not be cured by treatment, and that patients of European ancestry have a significantly higher probability of being cured than patients of African ancestry. In addition to limited efficacy, treatment is often poorly tolerated because of side effects that prevent some patients from completing therapy. For these reasons, identification of the determinants of response to treatment is a high priority. Here we report that a genetic polymorphism near the IL28B gene, encoding interferon-lambda-3 (IFN-lambda-3), is associated with an approximately twofold change in response to treatment, both among patients of European ancestry (P = 1.06 x 10(-25)) and African-Americans (P = 2.06 x 10(-3)). Because the genotype leading to better response is in substantially greater frequency in European than African populations, this genetic polymorphism also explains approximately half of the difference in response rates between African-Americans and patients of European ancestry.

Current Funded Projects

Principal Investigator: Scott Palmer, MD, MHS, Duke University Project Title: Immune monitoring tests for lung transplant patients Objective: Develop immune profiling tests to guide anti-viral and immunosuppressant therapy for lung transplant patients. Antigen stimulation and flow cytometry assays will be used to assess patients’ immune status against cytomegalovirus and a novel biomarker of organ rejection.

Principal Investigator: Virginia Kraus, MD, PhD, Duke University Project Title: Development of laboratory tests indicating risk of osteoarthritis progression Objective: This project is designed to deliver the first diagnostic panel to revolutionize the treatment, management, and care of patients with osteoarthritis. With the ability to identify aggressive, progressive osteoarthritis, it will become possible to deliver a personalized medicine treatment strategy and help alleviate the suffering caused by this chronic and debilitating disease.

Principal Investigators: John Sampson, MD, PhD, MHS, Duke University, and Duane Mitchell, MD, PhD, Duke University Project Title: Cytomegalovirus (CMV) as a biomarker for glioblastoma Objective: Determine whether CMV infection and related immune responses are prognostic biomarkers for patients with glioblastoma multiforme. Viral load (plasma and tumor) plus antigen stimulation and flow cytometry assays will be evaluated for management of glioblastoma patients based on CMV status.

Principal Investigator: J. Brice Weinberg, MD, Duke University Project Title: Biomarker panels for management of chronic lymphocytic leukemia Objective: Identify prognostic biomarkers for progression of early, indolent chronic lymphocytic leukemia to more advanced stages requiring chemotherapy. A variety of cell-based assays will be developed to monitor disease progression and guide chemotherapy for chronic lymphocytic leukemia.



Jeffrey Shuster, PhD [email protected]

www.biomarkerfactory.com

a source of funding for translational medicine in...

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